Preparation of x-aryl-x-car



Patented Nov. 1, 1949 a UNITED STATES PATENT QFFI CE PREPARATION OF 4-ARYL-4-G'AR- BALKOXY-PIPERIDINES Hans Kaegi, Basel, and Karl Miescher, Riehen,

Switzerland, assignors to Ciba Pharmaceutical Products Inc., Summit, N. J.*, a corporation No Drawing. Application May'i, 1945,

Serial No. 592,536 In Switzerland August 28, 1944 6 Claims. (01. 260-294) 1 2 I It is known that aliphatic a-betaines, but not dinium' salts, the manufacture of which is de- ;8- and 'y-betaines, can be transposed on heating scribed in application Serial No. 530,742; filed into dialkylamino acetic acid esters (Berichte April 12, 1944, now Patent 2,486,792. These piper'-' der deutschen chemischen Gesellschaft, vol. 35, idinium salts can be easily saponified, for exampage 584). An analogous transformation of the pie, with mineral acids; The corresponding betrimethyl-ortho-, -meta or -para-benz-betaines taines are obtained by subsequent treatment with into the corresponding dimethylaminobenzoic acid strong alkalies, for example, potassium hydroxide,

methyl esters can also be efiected (Berichte der calcium hydroxide, silver oxide and the like. The

deutschen chemischen Gesellschaft, vol. 6, page course of the reaction starting from 1:1-dimethyl- 585, and vol. 37, page 401). Such a, transformal0 -4-phenyl-4-cyano-piperidinium bromide is extion, however, can not be brought about with plained by the following scheme:

CqHu-C-GN sapouification, for CtH;C C 0 OH example, with H2804 of C 1 CH, 80 per cent strength 0 2 CH1 e. g. Ca(OH)g i --q CH: H, CH: CH:

N 1 cgtimn cg 510,11 CH! CtHt-C-COO CuHr-G\ 0O C6Hs-C+COOOHa C 2 CH: C 3 CH1. C 1 CH:

t M t I E? 1 E2 /C z Cg: -/CH'.'

f a o on, oft om CH! heterocyclic compounds, for examplaarecaidine- The following examples illustrate the invendimethyl-betaine and trigonelline, where decomtion,the parts being by weight: position occurs on heating with evolution of gas Emmple 1 (Berichte der deutschen chemischen Gesellschaft, vol. 35, page 584), The conversion of 21 pa ts of 1:1-dimethyl-4-phenyl-piperidinebetaines into corresponding esters thus takes 4-carb0Xy1i0 ac d betaine are heated to 250 C.

place only exceptionally. It had to be regarded a fraqtionatingtfiask in an air bath by usin as very little promising to subject 4-aryl-piperia te p t v h b e o s ot me dine-l-carboxylic acid betaines to this reaction, but dlstlnatlon Occurs dlrectly, a yellow Oil being as it was-to be assumed that a considerable dethus cbtamedwhich 'g Q tempera composition would occur, judging from the state ture; For the-further purification :the'product of the art described above may be subjected to a fractional'distillation in a According to the present invention 4-arylhlgh Q Q- There is t f y piperidine-i-carboxylic acid esters are surprisphenyl"plperldlne4'carboxyhc 3. methylesteringly Obtained in good yield by heating 40 This compound can be recrystallized from piperidinel-carboxylic acid betaines to a high hexane andl'lhen melts at temperature until rearrangement occum The betame used as starting material is me- In the starting materials the nucleus may pared from l:1-dn nethyl-i-phenyl 4 cyano be Substituted or unsubstituted, while methyl, piperidmium bromide obtainable according to the ethyl, propyl, an, benzyl phenylethyl and Simi process described inapplication Serial No. 530,742"

lar groups are attached to the piperidine nitrogen from dimfihylafmnoethyt Penzylcyanide, by atom. The piperidine nucleus may also contain Sapomficatlon Wlth Sulfurlc acld of 30 per cent further substimemi strength at 40 C. The sulfuric acid is pre- The transformation of the betames into the cipitated with calcium hydroxide, filtered; and

corresponding esters occurs as a rule at 200-250 h "filtrate is ap lat d. The remaining 1:1- 0. Lower temperatures are also sufficient in some d1methy1'4'phenyl'plPendme-l-caflfioxylic ac d cases. Adistillation can also be carriedout simulbeta'meJis crystaume mass Whlch s easily taneously with heating, at ordinary or reduced Somme 'f 9 i p es on pressure. The ester which has formed is often heatmg Wlthoutf a 'E mliltmg P distilled off directly, without the betaine having Instead of wlthsulfurw f 0 per cent previously melted. The transformation can also Strength. the y -p y 4 yano be effected in a solvent of high boiling point. Piperidinium de c n also be saponified by The 4-aryl-piperidine-4#carboxylie acid beboiling with 10-N hydrobromic acid or by heattaines used as starting materials are formed, for ing to 190-200 C. with methyl alcohol solution of example, by saponifying 4-ary1-4-cyano-pipericaustic potash. In the-former case the bromine" ion is combined wlth caustic potash solution after distilling off the hydrobromic acid in excess, in

the latter case the caustic potash solution Example 2 I When using in Example as starting material- 1:l-diethyl-4-phenyl-piperidine 4 carboxylic acid betaine, there is obtained by the dry distillation in good yield 1-ethyl-4-phenyl-piperidine-4- carboxylic acid-ethyl ester as an oil boiling at 115-117 C. under 0.07 mm. pressure.

Instead of subjecting the betaine to dry distillationit can also .be heatedin a solvent of highboiling point until ithas passed from the insoluble to the soluble state.

The betaine necessary for the reaction is obtained analogously to Example 1 from diethyl}.

aminoethyl-benzyloyanide. It is a rystalline mass which is easily soluble in water and alcohol and decomposes on heating without melting.

. Example 3 When using in Example 1 as starting material 1:1:2-trimethyl-4-phenyl' piperidine 4 car Instead of distilling the betaine, it may also be heated in a solvent of high boiling point, e. g. decaline. After complete dissolution the ester is isolated, for example, by shaking out with dilute acid.

The aforementioned betaine is obtained as a methyl-4-phenyl-4-cyano-piperidinium bromide producible itself from dimethyl-aminoethylbenzylcyanide and propylene-lzZ-dibromide.

Example 4 1: 1-methylbenzyl-4-phenyl-piperidine-4-car boxylic acid-betaine obtained from 1:1 methylbenzyl-4-phenyl-4-cyano piperidinum bromide by saponification as a glassy mass, is heated to 200? C. in a vacuum. The 1-methyl-4-phenylpiperidine-l-carboxylic acid-'benzylester is thereby distilled as an oil which yields a hydrochloride of melting point 171-173" C. In the catalytic Example 5 lzl-methyl allyl-4-phenyl piperidine-4-carboxy-lic acid-betaine, obtained as a crystalline mass from methylallylaminoethyl-benzylcyanide analogously to Example 1, is heated in a vacuum to-200- -250 C. until everything has distilled over. 1-methyl-4-phenyl-piperidine-4-carboxylic. acid allylester is thus obtained as an oil boiling at- 118 -120-C, under 0.05 mm. pressure.

t Example 6 When heating 1 :1-dimethyl-4-para-tolyl-piperidine-i-carboxylic acid-betaine as described in the foregoing Examples, the 1-methyl-4-paracarboxylic acid ester.

tolyl piperidinel carboxylic acid-methylester is obtained as an oil boiling at 118-120 C. under 0.15 mm. pressure which solidifies on cooling.

The betaine used for the transformation is obtained from para-tolylcyanide according to the above mentioned method as a crystalline mass.

Example 7 lzl-methyl ethyl-4-phenyl piperidine-4-carboxylic acid-betaine obtained from methylethylaminioethyl benzylcyanide according to the above mentioned method as an amorphous mass is rapidly distilled without a vacuum. The 1-ethyl-4- phenyl-piperidinel-carboxylic acid-methylester can be separated from the distillate by fractionated distillation as a colorless oil boiling at 109 C. under 003mm. pressure. The hydrochloride of the ester melts at 204-205 C.

What we claim is:

1. Process for the manufacture of a 4-arylpiperidine-4-car-bloxylic acid ester, comprising heating a 4-aryl-piperidine-4-carboxylic acid betaine to a high temperature until rearrangement occurs, and recovering the 4-aryl-piperidine-4-canb-oxylic acid ester,

2. Process for the manufacture of a 4-arylpiperidinel-carboxylic acid ester, comprising subjecting a 4-aryl-piperidine-4-carboxylic a'cid betaine to dry distillation, and recovering the 4-aryl-piperidinel-carboXylic acid ester.

3. Process for the manufacture of a 4-arylpiperidine-4-carboxylic acid ester, comprising heating a 4-aryl-piperidine-4-carboxylic acid betaine to a high temperature until rearrangement occurs in the presence of a solvent of high boiling point, and recovering the 4-aryl-piperldine-4-car boxylic acid ester.

4. Process for the manufacture of a 4-aryl- I ieridine-4-carbox lic acid ester, com risin glassy mass by saponification of the 1:1:2-tr1- pp y D g subjecting a 4-aryl-piperidine-4-carboxylic acid covering the 4-aryl-piperidine-4-carboxylic acid ester.

5. Process for the manufacture of a 4-ary1- F piperidine-4-carvboxylic acid ester, comprising subjecting 1 1-dimethyl-4-phenyl-piperidine-4- carboxylic acid betaine to dry distillation in a vacuum, and recovering the 4-aryl-piperidine 4-car boxylic acid ester.

6. Process for the manufacture of a 4-arylpiperidine-4-car-boxylic acid ester, comprising subjecting 1 l-methyl ethyl-4-phenyl piperidine-4-carboxylic acid betaine to dry distillation, and recovering the 4-aryl-piperidine-4- HANS KAEGI. KARL MIESCHER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,129,264 Downing et a1 Sept. 6, 1938 2,217,846 Arthner et a] Oct. 15, 1940 2,310,109 Neu' Feb. 2, 1943 2,413,615 Fox Dec. 31, 1946 FOREIGN PATENTS Number Country Date 344,029 Germany Nov. 12, 1921' 463,578

Germany July 31, 1928 Certificate of Correction Patent No. 2,486,795 November 1, 1949 HANS KAEGI ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows:

Column 1, line 46, for piperidine read piperidtno; column 3, line 48, for piperidinum read piperid'in'ium; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Ofiico.

Signed and sealed this 7th day of March, A. D. 1950.

THOMAS F. MURPHY,

Assistant Oommiasz'oner of Patents. 

